Recommended phase 2 dose (RP2D) of HB-200 arenavirus-based cancer immunotherapies in patients with HPV16+ cancers.
Authors: Siqing Fu, Lisle Nabell, Alexander T. Pearson, Rom Leidner, Douglas Adkins, Marshall R. Posner, Jorge J. Nieva, Debra L. Richardson, Agustin Pimentel, Sanjay Goel, Stuart J. Wong, Alan Loh Ho, Ari Rosenberg, Matthew H. Taylor, Raghad Abdul-Karim, Corinne Iacobucci, Xiaoping Qing, Kia Katchar, Katia Schlienger, David G. Pfister
Journal: Journal of Clinical Oncology (2022)

2517 Background: Treatment options are limited for patients with recurrent or metastatic human papillomavirus 16 positive (HPV16+) cancers. Generation and maintenance of HPV16+ cancers requires stable expression of HPV16-specific E7 and E6 oncoproteins, which are also a source of tumor-specific immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein and infect antigen presenting cells to induce tumor-specific T cell responses. The Phase 1 part of this study of HB-200 therapy (HB-201 single-vector therapy and HB-202/HB-201 two-vector alternating therapy) was conducted to determine RP2D for further exploration alone or in combination with pembrolizumab. Methods: The Phase 1 part used a 3+3 dose escalation design with up to 3 dose levels (DLs) of HB-201 and 4 DLs of HB-202/HB-201 explored. Patients with HPV16+ head and neck squamous cell carcinoma (HNSCC) or with other HPV16+ cancers were evaluated. Safety, tolerability, immunogenicity, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST were assessed to determine RP2D. Results: As of January 2022, 65 patients with a median of 3 prior anticancer treatments have been enrolled in the Phase 1 part of the study. All had HPV16+ confirmed genotype; the most common primary site was oropharynx, followed by anal and cervix. Adverse events were generally mild or moderate. For HB-201, 3 DLs, 2 dosing schedules and 2 administration routes were assessed across 40 patients. At DL3 of HB-201 administered intravenously (IV), dose-limiting toxicity (DLT) occurred in 1/6 patients in the HNSCC group (Grade 4 encephalopathy, fully recovered) and 1/2 patients in the non-HNSCC group (Grade 3 rash, fully recovered). Preliminary safety, efficacy, and immunogenicity data support IV injection of DL3 (5 × 10 7 units) every 3 weeks (Q3W) as the RP2D for HB-201 single-vector therapy. For HB-202/HB-201, 4 DLs and 2 administration routes were assessed across 25 patients. At DL4 of HB-202/HB-201 IV, 1/5 subjects in the HNSCC group reported a DLT (Grade 4 hepatitis, recovering at time of discontinuation). RP2D for HB-202/HB-201 will be determined in the very near future. Tumor control, including partial response, have been observed in subjects treated with either HB-201 or HB-202/HB-201 as monotherapy. Conclusions: HB-201 and HB-202/HB-201 were generally well tolerated and showed preliminary antitumor activity in heavily pre-treated patients with HPV16+ solid tumors. DL3 was selected as RP2D for HB-201 monotherapy. In the Phase 2 part of the study a combination of HB-201 at 5 × 10 6 units IV Q3W with pembrolizumab is being tested in HPV16+ HNSCC patients. Clinical trial information: NCT04180215.